The present invention is concerned with certain trans-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]quinazolin-4-(3H)-one derivatives, a method of using same as anticoccidial agents, intermediates therefor, and a process for certain intermediates therefor.
Coccidiosis, a poultry disease, is caused by several species of protozoan parasites of the genus Eimeria, such as E. acervulina and E. tenella. In particular, E. tenella is the causative agent of a severe and often fatal infection of the ceca of chickens which is manifested by extensive hemorrhage, accumulation of blood in the cecum (a pouch between the large and small intestines) and the passage of blood in the droppings. Essentially, coccidiosis is an intestinal disease which is disseminated by birds picking up the infectious organism in droppings on contaminated litter or ground. By damaging the intestinal wall, the host animal is unable to utilize its food, goes off its feed, and in untreated cases the disease terminates in either the death of the animal or the survival of unthrifty birds known commonly as "culls."
Several classes of compounds have been reported to be useful as anticoccidial agents. Among these are various 6-azauracil derivatives (Miller, U.S. Pat. No. 4,239,888; summarizing several additional classes); trans-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]-4(3H)-quinazolinone (febrifugine; The Merck Index, Tenth Edition, monograph No. 3881); and trans-7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]-4-(3H)-qu inazolinone (halofuginone; The Merck Index, Tenth Edition, monograph No. 4479). Such anticoccidial compounds are more broadly defined by Waletzky et al., U.S. Pat. No. 3,320,124 (Re. 26,833); and Jolly et al., U.S. Pat. No. 4,252,947. European patent application 98589 broadly discloses structurally related hydrazine derivatives of trans-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]quinazolin-4(3H)-ones as anticoccidial agents.
Structurally related compounds are also reported to be useful in combatting theileriosis in cattle (Schein, U.S. Pat. No. 4,340,596). Although not in any manner specifically disclosed, the broad genus of Schein can be selectively chosen so as to define instant 6-trifluoromethyl-3-[3-(3-hydroxypiperid-2-yl)-2-oxopropyl]quinazolin-4(3H )-one. The present anticoccidial activity of the novel species is most surprising in view of the fact that the isomeric 7-trifluoromethyl analog (also defined by Schein's broad genus) is lacking in instant anticoccidial activity.
Structurally related compounds, including broad generic disclosure of 3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]quinazolin-4(3H)-ones substituted on the aromatic ring with halogen, trifluoromethyl, lower alkylthio, methoxy, phenoxy, and benzyloxy groups, have also been disclosed as antimalarial agents by Baker et al., U.S. Pat. No. 2,694,711; see also Baker et al., U.S. Pat. Nos. 2,651,632 and 2,796,417 for compounds related to present intermediates. Although not in any manner specifically disclosed, a number of the instantly claimed compounds can be defined by said genera, once having knowledge of the present invention. While Baker et al. ('711) specifically disclose the 5-trifluoromethyl analog (isomeric with the present 6-trifluoromethyl analog), it is noteworthy that that compound is lacking in present anticoccidial activity.